J Bone Miner Metab (2009) 27:234–239
`DOI 10.1007/s00774-009-0035-0
`
`O R I G I N A L A R T I C L E
`
`Comparison of the analgesic effects of bisphosphonates:
`etidronate, alendronate and risedronate by electroalgometry
`utilizing the fall of skin impedance
`
`Takuo Fujita Æ Mutsumi Ohue Æ Yoshio Fujii Æ
`Akimitsu Miyauchi Æ Yasuyuki Takagi
`
`Received: 12 December 2007 / Accepted: 11 July 2008 / Published online: 13 February 2009
`Ó The Japanese Society for Bone and Mineral Research and Springer 2009
`
`Abstract Analgesic effects of etidronate, alendronate and
`risedronate were compared in patients with osteoporosis
`and/or osteoarthritis by measuring the fall of skin imped-
`ance along with conventional subjective pain-estimation by
`visual rating scale (VRS). One hundred ninety-nine post-
`menopausal women consulting the Osteoporosis and
`Osteoarthritis Clinic of Katsuragi Hospital complaining of
`back and/or knee pain were randomly divided into four
`groups; Group A (49 subjects) given 5 mg/day alendronate,
`Group E (50 subjects) 200 mg/day etidronate, Group R (50
`subjects) 2.5 mg/day risedronate and Group P no bis-
`phosphonate. None of the four groups showed significant
`deviation from others as to age and parameters of bone
`metabolism. Proportions of subjects with osteoporosis was
`18–40%. Those with osteoarthritis of the spine and knee,
`higher than Grade II according to the Nathan and Law-
`rence-Kellgren scale,
`respectively, was 45 and 61%,
`respectively, without a significant difference among the
`four groups. Significant positive correlation was found
`between the fall of skin impedance and pain expressed
`in VRS. Attenuation of exercise-induced fall of skin
`impedance and also subjective pain expressed in VRS
`was greatest in Group E with a highly significant differ-
`ence from Groups A (P = 0.0002 and P \ 0.0001), R
`
`T. Fujita (&) M. Ohue
`Katsuragi Hospital, 250 Makami-cho, Kishiwada,
`Osaka 596-0842, Japan
`e-mail: fujita@katsuragi-hosp.or.jp
`T. Fujita Y. Fujii A. Miyauchi
`Calcium Research Institute, Osaka, Japan
`
`Y. Takagi
`National Hospital System,
`Hyogo Chuo Hospital, Hyogo, Japan
`
`123
`
`(P \ 0.0001 and P = 0.0014) and P (P \ 0.0001 and
`P \ 0.0001). Neither A nor R showed significant differ-
`ence from P as to the fall of skin impedance. Among the
`three bisphosphonates tested, etidronate appeared to be
`outstanding in analgesic effects.
`Keywords Pain Skin impedance Etidronate
`Alendronate Risedronate
`
`Introduction
`
`In addition to Paget’s disease with markedly augmented
`bone resorption [1], bisphosphonates inhibiting osteoclastic
`bone resorption have been reported to alleviate pain in
`various bone diseases such as multiple myeloma, skeletal
`metastases of malignancy, polyostotic fibrous dysplasia,
`and osteogenesis imperfecta [2–5]. Analgesic effects of
`bisphosphonates on more common bone and joint diseases
`such as osteoporosis and osteoarthritis were also reported
`[6–8], but so far have kept evading precise statistical
`analysis leading to sound evidence, probably on account
`of the lack of an accurate and objective quantitative mea-
`surement of pain.
`In the present study, alleviation of the fall of skin
`impedance, one of the pain-associated phenomena proba-
`bly mediated by the autonomic nervous system, was
`measured by using electroalgometry [9–12], along with the
`conventional pain estimation using VRS in four groups of
`subjects with osteoporosis and/or osteoarthritis treated with
`each of the three bisphosphonates commonly used in
`Japan; etidronate, alendronate and risedronate in addition
`to basic supplementation with calcium. As shown in our
`first report on the analgesic effect of etidronate [10], the
`safe dose of etidronate to achieve best analgesic effect,
`
`Grun. Exh. 1050
`PGR for U.S. Patent No. 9,408,862
`
`

`

`J Bone Miner Metab (2009) 27:234–239
`
`235
`
`200 mg/day on average, was higher than the customary
`dose for increasing BMD and preventing fracture, 200 mg
`for 2 weeks followed by 10 weeks interval or 33 mg/day
`on average.
`The dose of etidronate was therefore set at 200 mg/day
`on average, or 400 mg/day 2 weeks on, and 2 weeks off.
`A group treated with no bisphosphonate in addition to basic
`supplementation with calcium served as the control.
`
`Subjects and methods
`
`Test subjects
`
`This study was conducted on 199 subjects consulting the
`Osteoporosis
`and Osteoarthritis Clinic of Katsuragi
`Hospital complaining of back or knee joint pain. According
`to the time sequence of consultation, subjects were asked to
`participate in the study, after fully explaining its purpose,
`procedure and any risk involved. Those who consented
`were asked to start as members of one of the following
`four groups according to the time sequence of the study:
`Group A taking 5 mg/day alendronate, Group E taking
`200 mg/day etidronate (400 mg, 14 days on and 14 days
`off) Group R taking 2.5 mg/day risedronate and group P no
`bisphosphonate, in addition to baseline supplementation
`with 900 mg calcium/day, for 7 months.
`Dropout rates estimated by proportion of subjects lasting
`less than 3 months in the program were 30.6% in A, 28.0%
`in E, 24% in R and 26% in P, without a significant devi-
`ation according to v2-test at P [ 0.05. The study was
`approved by the Institutional Review Board of Katsuragi
`Hospital.
`
`Study methods
`
`Tests for homogeneity among the four groups
`
`As to dropout and metabolic background, as shown in
`Table 1, age, number of dropouts, serum Ca, serum urine
`
`Ca/Cr, bone-specific alkaline phosphatase (BAP), and urine
`N-terminal collagen type I fragments were recorded.
`Serum Ca was measured by OCPC colorimetry, serum P
`by (BAP) by CLEIA method, urinary Ca by OCPC color-
`imetry, urinary creatinine by enzyme method and urinary
`N-terminal peptide of type I collagen (NTx) by an enzyme-
`linked immunoassay. Lumbar bone mineral density
`(LBMD) was measured by using DPX (General Electric),
`and deviations from young adult mean (YAM) was cal-
`culated, as percentage and number of standard deviation
`(SD).
`
`Pain estimation
`
`As to skeletal background, as shown in Table 2, LBMD
`was measured by DPX (General Electric), proportion of
`subjects with spinal fracture and mean number of spinal
`fracture in 1 person are shown as indices of osteoporosis,
`and Nathan and Kellgren scores are recorded to evaluate
`the degree of osteoarthritis of
`the spine and knee,
`respectively.
`Skin impedance was measured by using Impedance
`Meter
`(General Devices, Ridgefield, NJ, USA). Two
`electrodes were placed on the skin, one on the palm and the
`other on the back of the hand, and the third indifferent
`electrode on the flexer side of the forearm. Impedance
`between the two electrode was expressed as K X. Exercise-
`induced changes of the impedance from the basal value
`obtained at a quiet sitting position were calculated.
`Regardless of the basal value, percentage fall on exercise
`was used as an index of pain. Subjective pain was esti-
`mated by visual analogous scale, a distance of 10 cm was
`divided into 100 equal sections. The highest and intolerable
`pain was given a score of 100 and absence of pain defined
`as 0. In order to evaluate subjective pain induced by
`exercise loading, basal value at a quiet sitting position was
`always set at 0, and whatever pain caused by exercise
`loading was expressed in VRS scale. The test subjects
`locate his or her pain on the scale at each test and recorded
`the result themselves. The room and building used for the
`
`Table 1 Age dropouts and metabolic background of the treatment groups
`
`Groups
`
`Treatment
`
`Age (years)
`
`Dropouts
`(%)
`
`SCa (mg/dl)
`
`SP (mg/dl)
`
`Urine (Ca/Cr)
`
`BAP (lg/l)
`
`Urine NTX
`nMBCE/mMCr
`
`A
`
`E
`
`P
`
`R
`
`Alendronate ? Ca
`
`67 ± 7.6
`
`Etidronate ? Ca
`
`Ca
`
`68 ± 7.6
`
`66 ± 8.0
`
`Risedronate ? Ca
`
`68 ± 9.0
`
`20
`
`30
`
`26
`
`20
`
`9.3 ± 0.56
`
`3.6 ± 0.35
`
`0.23 ± 0.13
`
`29.9 ± 13.0
`
`49.7 ± 24.6
`
`9.2 ± 0.35
`
`3.7 ± 0.42
`
`0.23 ± 0.16
`
`28.5 ± 11.4
`
`49.2 ± 24.7
`
`9.4 ± 0.54
`
`3.7 ± 0.42
`
`0.20 ± 0.12
`
`28.6 ± 12.8
`
`42.3 ± 22.2
`
`9.4 ± 0.42
`
`3.6 ± 0.42
`
`0.22 ± 0.18
`
`27.0 ± 9.7
`
`48.1 ± 22.6
`
`Difference among each group was non-significant by multiple comparison with ANOVA and v2-test for goodness of fit. SCa serum calcium, SP
`serum inorganic phosphorus, urine Ca/Cr ratio of urinary excretion of calcium and creatinine, BAP bone-specific alkaline phosphatase, Urinary
`NTX urinary excretion on of N-terminal peptide fragment of collagen type I. Dropouts: proportion of subjects who dropped out in less than
`3 month (%). Proportion of dropout was free of significant deviation among the four groups (v2 = 2.98 \ 7.815, df = 3, P [ 0.05)
`
`123
`
`

`

`236
`
`J Bone Miner Metab (2009) 27:234–239
`
`Table 2 Skeletal background of the treatment groups
`
`Bone evaluation
`
`Osteoporosis
`
`Groups
`
`Treatment
`
`LBMD
`(G/cm2)
`
`LBMD \ -2.5
`SD of YAM (%)
`
`LBMD \ 70%
`of YAM (%)
`
`Osteoarthritis
`
`Proportion of
`subjects with
`spinal
`fracture (%)
`
`Mean spinal
`fracture
`number
`
`Spinal
`(Nathan)
`32(%)
`
`Knee
`(Kellgren)
`32(%)
`
`A
`
`E
`
`P
`
`R
`
`Alendronate ? Ca
`
`0.838 ± 0.125
`
`20/49 = 40
`
`Etidronate ? Ca
`
`0.906 ± 0.150
`
`14/50 = 28
`
`Ca
`
`0.902 ± 0.144
`
`17/50 = 34
`
`Risedronate ? Ca
`
`0.828 ± 0.207
`
`18/50 = 36
`
`13/49 = 26
`
`10/50 = 20
`
`9/50 = 18
`
`15/50 = 30
`
`30.6
`
`28.0
`
`24.0
`
`26.0
`
`Mean ± SD
`
`0.42 ± 0.84
`
`0.52 ± 1.02
`
`0.46 ± 0.93
`
`0.36 ± 0.80
`
`27
`
`40
`
`55
`
`61
`
`63
`
`58
`
`63
`
`63
`
`45 ± 28
`
`61 ± 7
`
`LBMD lumbar bone mineral density less than -2.5 SD was set at \0.816 G/cm2 and less than 70% of YAM at \0.745 G/cm2. Analysis of
`variance and multiple comparison of LBMD values among the four groups revealed a significantly higher value in E than A by PLSD
`(P = 0.0380) but no significant difference by other tests including Scheffe, Bonferroni–Dunn; Dunnet, Tukey–Kramer, games–Howell and
`Student–Newman–Keuls. v2-test on mean LBMD among the four groups satisfied the requirement for goodness of fit (v2 = 5.87 \ 7.815,
`P [ 0.05, df = 3). Parameters of osteoporosis; proportions of subjects with LBMD lower than -2.5 SD of YAM (v2 = 2.173 \ 7.815,
`P [ 0.05, df = 3),
`those with LBMD lower than 70% of YAM (v2 = 3.872 \ 7.815, P [ 0.05, df = 3),
`those with spinal fracture
`(v2 = 0.878 \ 7.815, P [ 0.05, df = 3) and mean spinal fracture number (v2 = 3.09 \ 7.815, P [ 0.05, df = 3) were all free of significant
`deviation from among the four groups, satisfying the requirement for goodness of fit. As to the parameters on osteoarthritis, proportions of those
`with Nathan score for spinal osteoarthritis32 failed to satisfy the v2-test for goodness of fit (v2 = 15.66 [ 7.815, P \ 0.05, df = 3), apparently
`because of a lower value in group A. As to those with Kellgren score for knee osteoarthritis 32, no such deviation was noted
`(v2 = 0.300 \ 7.815, P [ 0.05, df = 3)
`
`test was kept at a comfortably constant temperature and
`humidity by central heating. After measurement at a quiet
`sitting position on a chair to obtain basal level of skin
`impedance to obtain the basal preloading value, the test
`subject was asked to stand up, bend the knee, walk about
`50 steps on a flat floor, climb up about 10 steps of stairs,
`climb down the same height,
`lie down supine on an
`examination table and stand up again, with measurement of
`the impedance after each exercise. A mean of responses to
`all exercises over the 7-month study period was used as the
`mean exercise-induced fall of skin impedance in each
`group.
`
`Statistical procedures
`
`Statistical analysis was carried out by using Statview 5.0,
`SAS Institute, Cary, NC, USA), Fisher’s protected least
`significance difference (PLSD), Scheffe, Bonferroni–Dunn,
`Dunnet, Tukey–Kramer, Games–Howell and Student–
`Newman–Kauls methods were used following ANOVA.
`v2-test was also applied to evaluate difference in proportion
`among the four groups.
`
`Results
`
`A moderate correlation was found between the degree of
`pain measured by the fall of skin impedance and the degree
`of subjective pain estimated by VRS; correlation coeffi-
`cient r = 0.239 in 400 pairs of measurement, P \ 0.0001.
`
`The groups were apparently homogeneous as to age,
`serum Ca, P, BAP, urinary N-terminal peptide of Type 1
`collagen without significant difference among the four
`groups (Table 1).
`As shown in Table 2, analysis of variance and multiple
`comparison of LBMD among the four groups revealed a
`significantly higher value in E than A (P = 0.0380) by
`PLSD, but no significant difference in any other combi-
`nations. Other methods of analysis failed to detect any
`deviations. v2-test also revealed no significant deviations of
`proportions of subjects with LBMD less than -2.5 SD of
`YAM and 70% of YAM among the four groups. Propor-
`tions of subjects with spinal fractures (%) and mean
`number of fractures in the whole group were also free of
`significant deviation in view of the satisfactory goodness of
`fit.
`
`Osteoarthritis of the spine according to Nathan’s score
`on X-ray pictures indicated a significantly lower proportion
`of subjects with scores 2 from others only in group A. No
`deviations among the four groups were noted in Kellgren
`scores on knee osteoarthritis. Basal skin impedance before
`exercise loading changing in response to daily environ-
`mental and physiological factors, but nevertheless serving
`as a base for the decrease of skin impedance in response to
`exercise, was free of significant differences through the
`course of treatment among the four groups, as shown in
`Fig. 1.
`As shown in Fig. 2, the degree of pain measured by the
`fall of skin impedance was markedly attenuated after
`administration of etidronate (E) as shown by the percentage
`
`123
`
`

`

`J Bone Miner Metab (2009) 27:234–239
`
`237
`
`Changes of Basal Skin Impedance
`Prior to Exercise Loading in Each Test Group
`
`of pre
`%
`treatment value
`
`160
`
`150
`
`140
`
`142
`
`±
`127
`
`±
`137 159
`
`±
`150 141
`
`±
`145 156
`
`lllo
`
`E
`
`A
`
`P
`
`R
`±
`Mean SD
`
`Fig. 1 Changes of basal skin impedance prior to exercise loading in
`each test group. Basal skin impedance prior to exercise loading served
`as the baseline for the calculation of the ‘‘fall of impedance’’ which is
`used as the scale for exercise-induced pain. Group A consisted of 49
`subjects treated with 5 mg/day alendronate, Group E 50 subjects
`treated with 200 mg/etidronate, Group P 50 subjects given no
`bisphosphonate and Group R treated with 2.5 mg/day risedronate.
`Basal skin impedance expressed as percentage of pre-treatment value
`on the vertical axis showed no significant difference among the four
`groups (Bonferroni–Dunn and Scheffe multiple comparison tests)
`
`skin impedance after/before treatment of
`change of
`-29.5 ± 43.2% (Mean ± SD), significantly higher than
`after administration of no bisphosphonate (P), ?4.4 ±
`18.9% (P \ 0.0001), after administration of risedronate of
`-0.7 ± 26.4% (P \ 0.0001) and after administration of
`alendronate, -7.1 ± 24.3% (P \ 0.0001), but no signifi-
`cant difference was found among these three groups A,
`
`P and R. The analgesic effect of etidronate thus appears
`outstanding among these four groups.
`As shown in Fig. 3, etidronate also showed the most
`pronounced pain-attenuating effect on subjective pain,
`-41 ± 34% (Mean ± SD)
`expressed
`as
`percentage
`decrease from the level/before treatment significantly
`greater than after administration of no bisphosphonate,
`-7 ± 40% (P \ 0.0001)
`(P), after administration of
`alendronate, -9 ± 41% (P \ 0.0001)
`(A) and after
`administration of risedronate, -21 ± 55% (P = 0.0003)
`(R). Subjective pain was not significantly different between
`A and P and also A and R.
`
`Discussion
`
`Homogeneity of the four groups of test subjects as to met-
`abolic factors appeared to be reasonable as shown in
`Table 1. As to the bone and joint factors, LBMD appeared
`slightly lower in group A than E (P = 0.0380) by PLSD, but
`not by other methods including Tukey–Kramer test, despite
`an impression of slightly higher values in E and P, than A
`and R. v2-test for goodness of fit revealed no significant
`deviations among the four groups as to the proportions.
`Subjects with LBMD less than of -2.5 SD or 70% of YAM,
`proportions of those with spinal fracture, mean number of
`factures in each group, and the degree of osteoarthritis of the
`spine and knee were also free of significant deviations,
`except for spinal osteoarthritis evaluated by Nathan method,
`apparently due to less frequent spinal osteoarthritis than
`others. With some reservation of these problems on the
`
`Fig. 2 Changes of percentage
`attenuation of the exercise-
`induced fall of skin impedance
`through the course of the
`treatment in the four groups
`shown in Fig. 1. On the vertical
`axis, mean ± SD of all values
`through the course of treatment
`is shown as 100% after/before
`treatment impedance. The four
`groups were apparently
`homogenous as to the pain
`expressed as fall of impedance
`prior to treatment
`(v2 = 0.456 \ 7.815,
`P [ 0.05). The fall from the
`horizontal bar shows
`attenuation by the treatment.
`Etidronate achieved
`significantly more attenuation of
`pain than placebo, alendronate
`and risedronate. A and R
`showed no significant difference
`from P
`
`Attenuation of the Exercise - Induced Fall
`Changes of
`%
`of Skin Impedance through the Course of Treatment
`
`<0.0001
`
`<0.0001
`0.0136 NS
`
`<0.0001
`7
`
`0.2204 NS
`
`0.0959 NS
`
`±
`- 7.1 24.3
`
`±
`- 29.5 43.2
`
`±
`+ 4.4 18.9
`
`±
`- 0.7 26.4
`
`P-values
`
`% Change
`of Pain
`Exprressed
`as Fall of Skin
`Impedance
`
`30
`20
`
`10
`
`0
`
`-10
`
`-20
`
`-30
`
`Actual
`
`Before
`Treatment
`Value After
`Treatment
`
`21.4
`
`19.9
`
`28.0
`
`19.8
`
`A
`E : etidronate
`A : alendronate
`P : No bisphoshonate R : risedronate
`
`E
`±
`Mean SD
`
`21.5
`
`22.5
`
`P
`
`23.6
`
`23.5
`
`R
`
`Bonferroni– Dunn Multiple Comparison
`
`123
`
`

`

`238
`
`Fig. 3 Mean analgesic effects
`of bisphosphonates and placebo
`expressed as attenuation of the
`exercise-induced subjective
`pain in VRS. Etidronate also
`attenuated subjective pain
`significantly better than the
`remaining three agents. Neither
`risedronate nor alendronate was
`significantly more effective to
`attenuate subjective pain than
`placebo. Goodness of fit among
`the four groups as to subjective
`pain prior to the exercise
`loading may give rise to
`questions unlike pain expressed
`as fall of skin impedance
`according to v2-test
`(v2 = 8.748 [ 7.815, P \ 0.05)
`probably because of a wide
`variation including high values
`in group E
`
`J Bone Miner Metab (2009) 27:234–239
`
`Attenuation of the Exercise - Induced
`Changes of
`%
`Subjective pain ( VRS ) through the Course of Treatment
`
`0.1335 NS
`
`<0.0003
`
`P-values
`
`<0.0001
`
`~
`-----
`
`<0.0001
`1
`0.7972 NS
`
`1
`
`r-
`
`NS
`
`0.04781
`
`±
`- 9 41
`
`±
`- 41 34
`
`±
`- 7 40
`
`±
`- 21 55
`
`After / Before
`% Change
`of VRS
`
`0
`- 10
`- 20
`- 30
`- 40
`
`Actual
`
`Value
`
`Before
`Treatment
`After
`Treatment
`
`9.3
`
`8.5
`
`18.4
`
`10.9
`
`A
`E : etidronate
`A : alendronate
`P : No bisphoshonate R : risedronate
`
`E
`±
`Mean SD
`
`4.9
`
`4.6
`
`P
`
`8.8
`
`7.0
`
`R
`
`Bonferroni– Dunn Multiple Comparison
`
`goodness of fit among the four groups as to the bone and
`joint factors, which may be inevitable to some extent in
`view of the complexity of the clinical pictures, we pro-
`ceeded to analyze the difference in the effects of
`bisphosphonates in each group.
`The outstanding analgesic effect of bisphosphonates
`especially etidronate was evident both by conventional
`visual rating scale (VRS) on subjective pain and recently
`introduced electroalgometry utilizing the fall of skin
`impedance. Further comparison of the analgesic effects of
`various bisphosphonates may be worthwhile and efforts
`should be directed to developments of new bisphospho-
`nates with better analgesic effects.
`Inhibition of bone resorption was reported to reduce
`bone pain by bisphosphonate [13] and osteoprotegerin [14].
`The analgesic effect of bisphosphonate in osteoporosis and
`osteoarthritis has not been fully explained. Osteoclasts
`create an acid environment through releasing hydrogen
`ions on their bone-resorbing activity, and these H ions may
`cause pain through activation of the acid-sensing ion
`channels transmitting pain sensation. Acidosis is associated
`with augmented pain sensation [15]. In rats inoculated with
`MRMT-1 breast cancer, hyperalgesia was significantly
`reduced by zoledronic acid, one of the new bisphospho-
`nates [16].
`In terms of inhibitory action on bone resorption and
`increase of bone mineral density, newer bisphosphonates
`such as alendronate and risedronate apparently do better
`than the first generation etidronate. Distinct advantage of
`etidronate in terms of analgesic effects, despite support by
`clinical experience, was therefore somewhat unexpected.
`
`The daily dose employed in the clinical study, much higher
`for etidronate than the two others, may also have contrib-
`uted to the superior analgesic effect of etidronate.
`Since osteoporosis and osteoarthritis frequently coexist
`especially in postmenopausal
`females and males and
`females of advanced age, and osteoporosis known as a
`silent epidemic is usually free of pain until fracture and
`deformity occurs, osteoarthritis may also be responsible in
`the test subjects in the present study at least in part and the
`dose of bisphosphonates to achieve analgesic effects should
`be considered separately from that for increasing BMD or
`reducing fracture.
`The study on the analgesic effects of bisphosphonates
`should be extended to include many other new bisphos-
`phonates to find the best means to control pain in
`osteoporosis and osteoarthritis [17]. The mechanism of
`analgesic action of bisphosphonate should also be clarified
`further to help designing new effective analgesic bisphos-
`phonates, including the reason for the different dose levels
`required for BMD-increasing and analgesic effects.
`For this purpose, the new attempt of quantifying pain by
`measuring the fall of skin impedance employed in the
`present study should be explored and tested further, as the
`only objective and quantitative method assessing one of the
`pain-associated physiological phenomena, without entirely
`relying upon the purely subjective ‘‘pain scale’’, readily
`influenced by daily fluctuations of the mood and emotional
`state and even deliberately false statement by test subjects
`cannot be absolutely excluded.
`Limitation of the present clinical pilot study may consist
`in the homogeneity among the four groups not entirely free
`
`123
`
`

`

`J Bone Miner Metab (2009) 27:234–239
`
`239
`
`from scrutinizing questions, although tests for goodness of
`fits generally supported it except
`in limited instances.
`Further confirmation by large scale study may be in order.
`Dependence on the wild changes of VRS values on sub-
`jective pain alone may not be adequate for pain evaluation.
`
`References
`
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